2-Bromopyridine → alpha-(2-(1-Pyrrolidinyl)ethyl)-alpha-(p-tolyl)pyridine-2-methanol

HRID 1803086Notes

Reaction equation

HRID 1803086 reaction equation
C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:28])[CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1>CCCCCC.C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)([OH:28])[CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1

Participants

6

Reactant 3

HCID 79732-BromopyridineHCID 30249794'-Methyl-3-pyrrolidinopropiophenoneHCID 178418339Butyllithium

Product 1

HCID 11970576alpha-(2-(1-Pyrrolidinyl)ethyl)-alpha-(p-tolyl)pyridine-2-methanolYield 80.6%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 8058HexaneSolvent

Conditions

Temperature
-40 °C

Procedure

400 ml of toluene is charged into a round-bottom flask, which is cooled to −40° C. and then solution of n-butyllithium (76.6 g) in hexane is added and the temperature of the reaction mixture is maintained at −40° to −50° C. 2-Bromopyridine (189.2 g) is then added to the reaction mixture and the temperature is maintained at −65° to −55° C. for 35 to 45 minutes. 200 g of 4′-methyl-3-pyrrolidinopropiophenone in 200 ml of toluene is added to the reaction mixture in the R.B. flask. The reaction mass is stirred at −65° to −55° C. for 2 hours and it is further stirred for 1 hour at −40° to −50° C. The reaction mass is quenched in ice water and HCl is added slowly at 10° to 20° C. to get a clear solution. The aqueous layer is separated and it is added slowly to NaOH in the R.B. flask at 15° C.-20° C. The reaction mass is stirred for half an hour and the precipitated solid is filtered off. The solid is transferred into a round-bottom flask and then 500 ml of methanol is added. The reaction mass is refluxed at 60° C. for half an hour and the mass is cooled to 10°-20° C. The solid mass is filtered and dried under suction for one hour. On drying the solid compound at 70°-80° C. for 4 hours, 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidinopropan-1-ol (220 g, 80.5% yield) with 99.3% HPLC purity is obtained whose melting point is in the range of 115°-119° C.

Workup

  1. temperaturethe temperature of the reaction mixture is maintained at −40° to −50° C
  2. temperaturethe temperature is maintained at −65° to −55° C. for 35 to 45 minutes
  3. stirringit is further stirred for 1 hour at −40° to −50° C
  4. customThe reaction mass is quenched in ice water
  5. additionHCl is added slowly at 10° to 20° C.
  6. customto get a clear solution
  7. customThe aqueous layer is separated
  8. additionit is added slowly to NaOH in the R.B
  9. customat 15° C.-20° C
  10. stirringThe reaction mass is stirred for half an hour
  11. filtrationthe precipitated solid is filtered off
  12. customThe solid is transferred into a round-bottom flask
  13. addition500 ml of methanol is added
  14. temperatureThe reaction mass is refluxed at 60° C. for half an hour
  15. temperaturethe mass is cooled to 10°-20° C
  16. filtrationThe solid mass is filtered
  17. customdried under suction for one hour
  18. customOn drying the solid compound at 70°-80° C. for 4 hours

Sources & evidence

ORD record
ord-88a1181c37644021bd7506248ae6a4fb
Source dataset
uspto-grants-2013_01
Patent number
US08350045B2

Reaction notes

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